NM_000271.5(NPC1):c.2728G>A (p.Gly910Ser) AND Niemann-Pick disease, type C1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 22, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000674176.5

Allele description [Variation Report for NM_000271.5(NPC1):c.2728G>A (p.Gly910Ser)]

NM_000271.5(NPC1):c.2728G>A (p.Gly910Ser)

Gene:

NPC1:NPC intracellular cholesterol transporter 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q11.2

Genomic location:

Preferred name:

NM_000271.5(NPC1):c.2728G>A (p.Gly910Ser)

HGVS:

NC_000018.10:g.23539878C>T
NG_012795.1:g.51740G>A
NM_000271.5:c.2728G>AMANE SELECT
NP_000262.2:p.Gly910Ser
NC_000018.9:g.21119842C>T
NM_000271.4:c.2728G>A
O15118:p.Gly910Ser

Protein change:

G910S

Links:

UniProtKB: O15118#VAR_043249; dbSNP: rs768999208

NCBI 1000 Genomes Browser:

rs768999208

Molecular consequence:

NM_000271.5:c.2728G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Niemann-Pick disease, type C1
Synonyms:: NIEMANN-PICK DISEASE WITHOUT SPHINGOMYELINASE DEFICIENCY; Niemann-Pick disease with cholesterol esterification block; Niemann-Pick disease, chronic neuronopathic form; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009757; MedGen: C3179455; Orphanet: 646; OMIM: 257220

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000799465	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Apr 18, 2018)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 29197565, 26108224, 27706244, 12401890, 28802248, 28480683, 28193631 Citation Link,
SCV000934824	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 22, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12401890, 26108224, 27706244, 28480683, 28802248, 29197565, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000799465

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Apr 18, 2018)

unknown

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000934824

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 22, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells.

Pipalia NH, Subramanian K, Mao S, Ralph H, Hutt DM, Scott SM, Balch WE, Maxfield FR.

J Lipid Res. 2017 Apr;58(4):695-708. doi: 10.1194/jlr.M072140. Epub 2017 Feb 13. Erratum in: J Lipid Res. 2017 Sep;58(9):1932. doi: 10.1194/jlr.M072140ERR.

PubMed [citation]

PMID:: 28193631
PMCID:: PMC5392745

Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in fibroblasts.

Tarugi P, Ballarini G, Bembi B, Battisti C, Palmeri S, Panzani F, Di Leo E, Martini C, Federico A, Calandra S.

J Lipid Res. 2002 Nov;43(11):1908-19.

PubMed [citation]

PMID:: 12401890

See all PubMed Citations (8)

Details of each submission

From Counsyl, SCV000799465.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000934824.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 910 of the NPC1 protein (p.Gly910Ser). This variant is present in population databases (rs768999208, gnomAD 0.002%). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 12401890, 26108224, 27706244, 28480683, 28802248, 29197565). ClinVar contains an entry for this variant (Variation ID: 268187). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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